Sonic Muscle Regeneration

声波肌肉再生

• 批准号: 7682852
• 负责人: Roberto Pola
• 金额: $ 22.74万
• 依托单位: STEWARD ST. ELIZABETH'S MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7682852
• 关键词: Adult; Affect; Bone Marrow; Clinical; DNA; Data; Development; Direct Lytic Factors; Duchenne muscular dystrophy; Elderly; Embryo; Embryonic Development; Epithelial; Erinaceidae; Family suidae; Fibroblasts; Fibrosis; Gene Transfer; Human; In Vitro; Individual; Injection of therapeutic agent; Injury; Ischemia; Lead; Life; Light; Limb structure; Mechanics; Mesenchymal; Modeling; Molecular; Mus; Muscle; Muscle satellite cell; Muscular Dystrophies; Myocardial Ischemia; Myocardial Revascularization; Myopathy; Natural regeneration; Organ; Outcome; Pathology; Pathway interactions; Pattern; Physiological; Plasmids; Play; Process; Production; Regulation; Relative (related person); Reporting; Rodent; Role; Signal Pathway; Signal Transduction; Skeletal Muscle; Skeletal muscle injury; Stem cells; Testing; Therapeutic; Up-Regulation; Validation; Vascular Endothelial Growth Factors; Wound Healing; age related; aged; angiogenesis; base; cell type; clinically relevant; cyclopamine; cytokine; design; gene therapy; heart function; improved; in vivo; inhibitor/antagonist; injured; macrophage; mdx mouse; molecular marker; morphogens; mouse model; muscle degeneration; muscle regeneration; myogenesis; neovascular; neovascularization; public health relevance; receptor; reconstitution; regenerative; repaired; research study; response; sarcopenia; satellite cell; self-renewal; stem cell population; therapeutic angiogenesis; vasculogenesis

DESCRIPTION (provided by applicant): Sonic hedgehog (Shh) is a crucial regulator of organ development during embryogenesis. Recently, we demonstrated that the Shh signaling is post-natally recapitulated upon ischemic injury of the adult skeletal muscle. We also found that the inhibition of the Shh pathway during skeletal muscle ischemia results in decreased angiogenic response. We also demonstrated that exogenous administration of Shh induces therapeutic angiogenesis in the ischemic muscle of old mice and that Shh intramyocardial gene transfer preserves heart function in myocardial ischemia, by enhancing neovascularization, reducing fibrosis, and increasing mobilization of bone marrow-derived endothelial progenitor cells. More recently, we have generated preliminary data showing that the Shh signaling pathway is also upregulated after mechanical and toxic injury of the skeletal muscle. In this setting, different cell types, including fibroblasts, macrophages, and satellite cells, respond to Shh activity. The aims of this proposal are: 1) to investigate the functional role of Shh on the activation of both angiogenesis- dependent and independent mechanisms that are important for muscle regeneration; 2) to evaluate whether treatment with Shh improves regeneration in mouse models of skeletal muscle degeneration and dystrophy. The embryonic Shh signaling will be reconstituted by gene transfer of naked DNA encoding human Shh in the skeletal muscle of mice affected by ischemia, age- related muscle degeneration, or muscle dystrophy. We hypothesize that the activation of the Shh pathway will result in broad beneficial effects to muscle regeneration and repair, consistent with the role of this morphogen in embryogenesis, such as stimulation of angiogenesis and vasculogenesis, activation of muscle regulatory factors, and enhancement of the activity of muscle satellite cells. PUBLIC HEALTH RELEVANCE: We will use mouse models that are representative of important muscle diseases in humans. In particular, we will induce reconstitution of the embryonic Shh signaling in old mice (that have impaired muscular regenerative capacity, as observed in elderly individuals) and in mdx mice (a model of Duchenne muscular dystrophy). The results of this study might demonstrate that treatment with Shh may have considerable therapeutic potential in individuals with skeletal muscle diseases, by triggering expression of multiple trophic factors and engendering tissue repair in the adult.

描述（由申请人提供）：Sonic刺猬（SHH）是胚胎发生过程中器官发育的关键调节剂。最近，我们证明了成年骨骼肌缺血性损伤后，SHH信号是在后期概括的。我们还发现，在骨骼肌缺血期间对SHH途径的抑制会导致血管生成反应降低。我们还证明，SHH的外源给药可在老鼠缺血性肌肉中诱导治疗性血管生成，而SHH心脏内心脏基因转移可以通过增强新生血管性，减少纤维化和减少骨胶质胶质骨质骨质质源性细胞的动员来维护心肌缺血的心脏功能。最近，我们产生了初步数据，表明骨骼肌的机械和毒性损伤后，SHH信号通路也被上调。在这种情况下，包括成纤维细胞，巨噬细胞和卫星细胞在内的不同细胞类型对SHH活性有反应。该提案的目的是：1）研究SHH在激活血管生成和独立机制中对肌肉再生很重要的功能； 2）评估SHH治疗是否可以改善骨骼肌变性和营养不良的小鼠模型中的再生。胚胎SHH信号传导将通过编码人类SHH的基因转移在受缺血，与年龄相关的肌肉变性或肌肉营养不良的小鼠的骨骼肌中的基因转移来重构。我们假设SHH途径的激活将对肌肉再生和修复产生广泛的有益作用，这与该形态发生在胚胎发生中的作用一致，例如血管生成和血管生成，肌肉调节因素的激活以及肌肉卫星细胞活性的激活。 公共卫生相关性：我们将使用代表人类重要肌肉疾病的老鼠模型。特别是，我们将诱导旧小鼠的胚胎SHH信号的重构（如在老年人中所观察到的那样，肌肉再生能力受损）和MDX小鼠（Duchenne肌肉营养不良的模型）。这项研究的结果可能表明，SHH治疗通过触发多种营养因子的表达并引起成人的组织修复，在骨骼肌疾病的个体中可能具有相当大的治疗潜力。

项目成果

Sonic hedgehog gene therapy increases the ability of the dystrophic skeletal muscle to regenerate after injury.

声波刺猬基因疗法可提高营养不良的骨骼肌受伤后的再生能力。

• DOI: 10.1038/gt.2014.13
• 发表时间: 2014
• 期刊: Gene therapy
• 影响因子: 5.1
• 作者: Piccioni,A;Gaetani,E;Palladino,M;Gatto,I;Smith,RC;Neri,V;Marcantoni,M;Giarretta,I;Silver,M;Straino,S;Capogrossi,M;Landolfi,R;Pola,R
• 通讯作者: Pola,R

Sonic hedgehog therapy in a mouse model of age-associated impairment of skeletal muscle regeneration.

声波刺猬疗法对年龄相关的骨骼肌再生损伤的小鼠模型进行治疗。

• DOI: 10.1093/gerona/glt076
• 发表时间: 2014
• 期刊: The journals of gerontology. Series A, Biological sciences and medical sciences
• 作者: Piccioni,Andrea;Gaetani,Eleonora;Neri,Valentina;Gatto,Ilaria;Palladino,Mariangela;Silver,Marcy;Smith,RoyC;Giarretta,Igor;Pola,Enrico;Hlatky,Lynn;Pola,Roberto
• 通讯作者: Pola,Roberto